Chromosomally unbalanced sperm contribute significantly to the frequency of heteroploidy in live-births and fetal loss. Studies of chromosomes in human sperm after in vitro fertilization of hamster eggs have shown high rates of heteroploidy with significant individual differences in the frequency. These studies have been interpreted with caution because of the interspecies cross and the conditions of fertilization. Nevertheless, they suggest either in vivo sperm selection or postzygotic loss of unbalanced embryos to account for the high heteroploid rates. To date, the evidence for sperm selection has been conflicting. However, recent cytogenetic studies of one-cell zygotes resulting from sperm aging provide strong evidence for a sperm selection process that can be relaxed after sperm aging in the male. These studies also suggest that the individual variation in human sperm heteroploidy seen in the in vitro studies might have resulted from variation in sperm aging in the males tested. Sperm selection and possible underlying mechanisms will be investigated herein using a new approach by testing the following hypotheses in the mouse. 1) There is a selection mechanism operating against aneuploid sperm from translocation carriers and it can be relaxed after aging sperm in the male. 2) Individual differences in the frequency of fertilizing heteroploid sperm from chromosomally normal males may be related to the age of the sperm population at the time of fertilization. 3) Due to a maturational delay, chromosomally unbalanced sperm in unaged populations are at a selective disadvantage in effecting fertilization in vivo but not in vitro. 4) Differences between heteroploid and normal sperm in maturation and/or senescence levels may be involved in sperm selection. The first cleavage assay which allows analysis of the fertilizing sperm genome (as well as the female) in an intraspecies cross, and eliminates the question of postzygotic loss will be used for chromosome studies. Aged and unaged haploid and diploid sperm will be measured cytochemically for differences in the nucleoprotein structure as a function of maturity. Differences in their cAMP content as a function of maturation and senescence will be measured using a radioimmunoassay. The study with in vitro fertilization is important in light of its increasing use in man while that with translocation carriers should be of interest to genetic counselors.